Please contact Stephen Pettitt at reversions[at]icr.ac.uk

Do not send patient-identifying information

About this site

This database is a collection of published reversion mutation events in homologous recombination genes in cancer. It is maintained by Stephen Pettitt, Gene Function Laboratory, Institute of Cancer Research, London SW3 6JB.

For further details and to cite this work, please see the publication in Cancer Discovery:

Pettitt, S. J., Frankum, J. R., Punta, M., Lise, S., Alexander, J., Chen, Y., et al. (2020). Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance. Cancer Discovery, 10(10), 1475–1488.

http://doi.org/10.1158/2159-8290.CD-19-1485

Methods

Cases were collected from a review of published literature and annotations standardised to a single reference transcript. Secondary mutations are also annotated to the reference transcript. Mutations in repeated regions were annotated at the most 3' position possible. Microhomology use was defined as one or more bases that can be aligned equally well at either end of a deletion. Distances between pathogenic mutations were calculated as the smallest possible value.

The transcripts used for the codified annotations are: BRCA1, NM_007294.3; BRCA2, NM_000059.3; RAD51C, NM_058216.2; RAD51D, NM_002878.3 and PALB2, NM_024675_3. All transcript coordinates are given as coding sequence (CDS)-based annotations (aTG = position 1). Genomic coordinates (hg38) were retrieved using the HGVS CDS annotation on the transcripts above via the Ensembl VEP.

Information for Patients

About this site

Cancers with mutations in the BRCA1 and BRCA2 genes are known to respond to platinum-based drugs (e.g. cisplatin, carboplatin) or PARP inhibitors (e.g. olaparib, rucaparib or talazoparib). However there have been reports from clincal trials and other clinical studies of patients developing resistance to these drugs. In some cases, this occurs by the tumour cells acquiring a second mutation that compensates for the effect of the original mutation, meaning that the cancer effectively regains normal BRCA1 or BRCA2 function and is no longer sensitive to these drugs. The purpose of this project is to collect reports of these second mutations ("reversion mutations") in order to study these in greater depth. There is not currently a good mechanism for doctors or researchers to report these mutations, so we hope to provide an easy way to report and collect these.

How will this improve understanding of cancer treatment?

There are several questions that we hope to answer as the collection of reported reversion mutation grows:

• Not all BRCA1 or BRCA2 mutations are the same. Are some mutations more likely to acquire reversions than others? This may affect a patient's risk of developing drug resistance.
• Are there any patterns in the DNA sequence of reversion mutations that suggest how they arise? If so, we may be able to target the pathways involved to prevent or manage the development of resistance mutations.
• The reverted BRCA genes are not usually completely normal. Are there any common properties of the reverted genes that we could target in order to provide further options for patients that develop resistance?

How can I find out more about the research?

If you have questions or comments about the project we would love to hear from you. Please contact us by email at reversions[at]icr.ac.uk.

If you have a BRCA1/2-associated cancer, or cancer with mutation in another homologous recombination gene such as RAD51C/D or PALB2, and are receiving PARP inhibitor or platinum treatment you may be able to contribute to the project. This would involve DNA sequence analysis of biopsies or blood samples. Please speak to your oncologist about how to get involved.

Information for Oncologists

About this site

There have been a number of case reports of patients with mutations in BRCA1, BRCA2 or other homologous recombination genes whose tumours have developed resistance to platinum or PARP inhibitor therapy. The most common known mechanism for this is acquisition of a second mutation that restores function of the HR gene (a reversion), typically a second deletion mutation that compensates for the pathogenic mutation or deletes it entirely. The purpose of this database is to unite and codify these reports in an effort to understand the emergence and characteristics of these reversion mutations.

Through the studty of further cases, we hope to be able to more accurately predict risk of reversion for a given pathogenic mutation. By studying the DNA sequence at the reversion site we hope to understand more about the DNA repair mechanisms involved in generating reversions in different genetic backgrounds. We are also engaged in laboratory research to better understand how to prevent or treat reversion mutations.

Contributing to the study

If you discover examples of reversion mutations in your clinical research you can submit them to the database. Reversion mutations are typically discovered in biopsies taken after progression on platinum or PARP inhibitors, or in circulating tumour DNA (ctDNA) sequencing from blood samples during or after treatment. If you have suitable biopsies and patient consent we would be happy to advise or collaborate to sequence these to look for reversion mutations.

Contact details

This site is run by Stephen Pettitt, Gene Function Laboratory, Institute of Cancer Research, London UK.

Please get in touch with any comments or questions: reversions[at]icr.ac.uk

1.2 - December 2021. Added Sorrels, Warner and Puhalla studies

1.1 - October 2020. Added Jacob et al. and Chen et. al. studies

v1.0 - As published Cancer Discovery/AACR 2020